Defining the role of the lateral reticular nucleus in skilled forelimb movement

项目摘要 灵巧的前肢任务的难度各不相同，但是否有人在执行一项拯救生命的任务 手术或喝杯咖啡，这些目标导向运动背后的神经机制是 人们对此知之甚少。先前的研究表明，当人们执行灵巧的前肢任务时，他们的四肢 当它穿过空间向目标移动时，运动是不断更新的。这一点始终如一且迅速 前肢动作的更新表明，反馈对于目标导向型前肢的成功至关重要 动静。然而，快速纠正的速度太快，不能完全用感觉反馈来解释， 因为感觉信号从身体到神经系统的传输存在延迟。神经学家 已经转向控制理论的工程原理来产生关于生物元素的假说 马达控制系统。一种有大量经验证据的理论是，在前肢运动期间，在内部 定向传出副本被发送到小脑，以便小脑可以预测 肢体的后续状态。一般来说，传出副本的证据被归类为电生理学。 和/或行为研究表明，运动输出调制比感觉反馈来得更快，但 目前尚缺乏对可能的神经结构的描述。缺乏描述假想神经的证据 结构作为发送、处理或接收传出副本，这是由于访问这些 结构。然而，在小鼠中使用分子遗传学工具，选择性地获得特定的细胞类型 在神经结构中，这使得潜在的传出复制电路更容易获得。为了理解 小脑是如何使用传出副本来产生对后续前肢位置的预测的，这是 迫切需要阐明传出拷贝的小脑前处理和组织。侧向 网状核(LRN)是一种小脑前结构，完全由发送苔藓纤维的神经元组成。 投射到小脑。LRN的一部分输入来自颈部的升支 固有脊髓中间神经元(PNS)。三叉神经节的特征是脊髓中间神经元接受下行运动 命令和发送分支轴突投射；一个分支下降到前肢运动神经元； 另一个分支上升到LRN，携带传出复制信息。因此，LRN是一个最优的 评估传出副本在熟练的前肢运动中的作用的目标。这项提议试图 通过1)干扰LRN功能，研究LRN在熟练前肢运动中的功能作用 熟练的前肢运动，以及2)使用体内多通道细胞外记录来表征传出 LRN中的复制组织和处理。除了剖析马达控制电路，这些发现可能会有所帮助 改善对患有毁灭性运动和神经缺陷的个人的诊断和治疗。 这些发现也可能为设计和改进神经假体提供策略。

Project Summary Dexterous forelimb tasks vary in their degree of difficulty, but whether someone is performing a life-saving surgery or reaching for a cup of coffee, the neural mechanisms that underlie these goal-directed movements are poorly understood. Previous studies have shown that as people perform dexterous forelimb tasks, their limb movement is constantly being updated as it traverses through space toward a target. This consistent and rapid updating of forelimb movement suggests that feedback is critical for the success of goal-directed forelimb movements. However, rapid corrections are performed too quickly to be explained purely by sensory feedback, because of delays in the transmission of sensory signals from the body to the nervous system. Neuroscientists have turned to engineering principles of control theory to generate hypotheses regarding the biological elements of motor control. One theory with considerable empirical evidence is that during forelimb movement, internally directed efference copies are sent to the cerebellum, so that the cerebellum can make predictions about the subsequent state of the limb. Generally, evidence for efference copies has been relegated to electrophysiology and/or behavior studies that demonstrate motor output modulation arriving faster than sensory feedback, but the characterization of putative neural structures is lacking. The dearth of evidence characterizing putative neural structures as either sending, processing, or receiving efference copies is due to the difficulties in accessing these structures. However, the use of molecular-genetic tools in the mouse, to selectively access specific cell types within a neural structure, has made potential efference copy circuits more accessible. In order to understand how the cerebellum is using efference copies to generate predictions about subsequent forelimb positions, it is imperative that the pre-cerebellar processing and organization of efference copies are elucidated. The lateral reticular nucleus (LRN) is a pre-cerebellar structure entirely composed of neurons that send mossy fiber projections to the cerebellum. A subset of the input to the LRN comes from the ascending branch of cervical propriospinal interneurons (PNs). PNs are characterized as spinal interneurons receiving descending motor commands and sending bifurcating axonal projections; one branch descending to forelimb motor neurons, and the other branch ascending to the LRN, carrying efference copy information. Therefore, the LRN is an optimal target for evaluating the role of efference copies in skilled forelimb movement. This proposal attempts to investigate the functional role of the LRN in skilled forelimb movement by 1) perturbing LRN function during skilled forelimb movement, and 2) using multi-channel in vivo extracellular recordings to characterize efference copy organization and processing in the LRN. Beyond dissecting motor control circuits, these findings may help improve diagnostics and therapeutics for individuals suffering from devastating motor and neurologic deficits. These findings may also provide strategies for designing and improving neural prostheses.